Atherosclerosis is the primary driver of cardiovascular and cerebral vascular diseases globally. Atherosclerotic plaques have been detected in multiple arterial locations, such as the aorta, carotids, and coronaries. However, it remains uncertain if there are variations in susceptibility and association among arteries of different calibers. Utilizing a spontaneous rhesus monkey model of metabolic syndrome (MetS), we assessed the susceptibility of atherosclerosis among the radial artery, femoral artery, and carotid artery and their correlation with coronary heart disease (CHD). The development of atherosclerosis in the three arteries mentioned above was evaluated by Intima-media thickness (IMT) and plaques using echo imaging over 6 years in a cohort of elderly monkeys with metabolic disorders. Coronary artery stenosis was assessed by coronary flow reserve (CFR) simultaneously. The diagnosis was further confirmed by histopathological examination, and RNA sequencing was employed to probe the transcriptional underpinnings of atherosclerotic development. The spontaneous development of atherosclerosis was observed in elderly monkeys, and the incidence of atherosclerosis was increased by three times in the MetS monkeys compared to the age-matched control group. During the 6-year follow-up, there was a notable increase in the IMT across all three arteries, with the radial artery showing the most pronounced thickening. Moreover, only the radial IMT correlated with CFR, suggesting its potential as a non-invasive diagnostic indicator for CHD. Histopathology confirmed the findings by echo imaging and identified different extracellular matrix (ECM) remodeling patterns in the arteries. In addition, transcriptomic analysis revealed that ECM remodeling and inflammation-related pathways were significantly upregulated in radial atherosclerotic samples, multiple inflammatory pathways were upregulated in the femoral lesion samples, and the carotid samples failed to enrich any pathways due to a lack of differentially expressed genes compared to the control samples. Non-human primates, which share extensive genetic and physiological similarities with humans, develop atherosclerosis spontaneously. This provides an invaluable platform for investigating the intricate mechanisms of arterial disease and evaluating potential treatments. Using the monkey model, we identified the radial artery as a sensitive indicator for assessing the occurrence and progression of atherosclerosis and coronary stenosis.

We aimed to study the mechanisms of GuBenZhiKe decoction (GBZKD) in treating Chronic obstructive pulmonary disease (COPD). Components of GBZKD were analyzed using liquid chromatography-mass spectrometry. ICR mice were exposed to cigarette smoke and administered lipopolysaccharide to establish a COPD model, followed by treatment with GBZKD. Lung function test, hematoxylin and eosin staining, electron microscopic observation, and immunohistochemistry assays were performed. The expressions of genes were examined using an antibody array, qRT-PCR and western blot. GBZKD reduced structural failure and inflammatory response in airways, terminal bronchioles, and alveoli of COPD mice. GBZKD suppressed the levels of α-SMA, MMP-9, TIMP-1, and MMP-9/TIMP-1 ratio in COPD mice. GBZKD suppressed the mRNA levels of JAK1 and STAT3, and elevated SOCS3 mRNA expression. GBZKD treatment significantly suppressed the protein levels of p-JAK1 and p-STAT3, and significantly elevated the SOCS3 protein expression. GBZKD alleviated respiratory tract injury by regulating the JAK-STAT pathway.

Background and aim: Previous study have demonstrated that Tangshen Formula (TSF) could attenuate colonic histomorphological remodeling in the diabetic rat model induced by high fat diet plus low dosage streptozotocin (STZ). However, it is not clear whether TSF has same effect on small intestine and the effect on biomechanical properties of bowel. The aim of this study is to investigate the effect of TSF on histomorphological and biomechanical remodeling of small intestine and colon by using Zucker Diabetic Fatty (ZDF) Rat model. Materials and methods: ZDF rats (obese fa/fa) with blood glucose higher than 11.7 mmol/L were divided into ZDF group (diabetic control group) and ZDF + TSF group (TSF treatment group), the later were intragastrically administered TSF. The ZDF rats (lean fa/+) were served as normal control (ZL) group. The rats in the ZL and ZDF groups were administered with saline. The experimental period covered from 8 weeks to 24 weeks. At the end of experiment, the ileal and colonic segments were studied in vitro. The histomorphometry and biomechanical parameters were measured. Results: Compared with ZL group histomorphologically, the wet weight per unit length, wall thickness, wall area and fractions of total and type I and type III collagen in different layers for both ileum and colon increased in ZDF group. Those increasing parameters were partially inhibited in ZDF + TSF group. Compared with ZL group biomechanically, ZDF and ZDF + TSF groups had smaller opening angle and residual strain in ileum, and bigger opening angle and residual strain in colon. Whereas the wall became softer in circumferential direction and stiffer in longitudinal direction for both ileum and colon. However, no difference of biomechanical parameters was found between ZDF and ZDF + TSF groups. Conclusion: The histomorphological and biomechanical remodeling of ileum and colon were happened in ZDF rats （obese fa/fa）. TSF could partly attenuate ileal and colonic histomorphological remodeling rather than biomechanical remodeling.

Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found that FOXP2 is overexpressed in human prostate cancer cells and prostate tumors, but its expression is absent in normal prostate epithelial cells and low in benign prostatic hyperplasia. FOXP2 is a FOX transcription factor family member and tightly associated with vocal development. To date, little is known regarding the link of FOXP2 to prostate cancer. We observed that high FOXP2 expression and frequent amplification are significantly associated with high Gleason score. Ectopic expression of FOXP2 induces malignant transformation of mouse NIH3T3 fibroblasts and human prostate epithelial cell RWPE-1. Conversely, FOXP2 knockdown suppresses the proliferation of prostate cancer cells. Transgenic overexpression of FOXP2 in the mouse prostate causes prostatic intraepithelial neoplasia. Overexpression of FOXP2 aberrantly activates oncogenic MET signaling and inhibition of MET signaling effectively reverts the FOXP2-induced oncogenic phenotype. CUT&Tag assay identified FOXP2-binding sites located in MET and its associated gene HGF. Additionally, the novel recurrent FOXP2-CPED1 fusion identified in prostate tumors results in high expression of truncated FOXP2, which exhibit a similar capacity for malignant transformation. Together, our data indicate that FOXP2 is involved in tumorigenicity of prostate.

Patients with chronic obstructive pulmonary disease (COPD) who exhibit elevated blood eosinophil levels often experience worsened lung function and more severe emphysema. This implies the potential involvement of eosinophils in the development of emphysema. However, the precise mechanisms underlying the development of eosinophil-mediated emphysema remain unclear. In this study, we employed single-cell RNA sequencing to identify eosinophil subgroups in mouse models of asthma and emphysema, followed by functional analyses of these subgroups. Assessment of accumulated eosinophils unveiled distinct transcriptomes in the lungs of mice with elastase-induced emphysema and ovalbumin-induced asthma. Depletion of eosinophils through the use of anti-interleukin-5 antibodies ameliorated elastase-induced emphysema. A particularly noteworthy discovery is that eosinophil-derived cathepsin L contributed to the degradation of the extracellular matrix, thereby leading to emphysema in pulmonary tissue. Inhibition of cathepsin L resulted in a reduction of elastase-induced emphysema in a mouse model. Importantly, eosinophil levels correlated positively with serum cathepsin L levels, which were higher in emphysema patients than those without emphysema. Expression of cathepsin L in eosinophils demonstrated a direct association with lung emphysema in COPD patients. Collectively, these findings underscore the significant role of eosinophil-derived cathepsin L in extracellular matrix degradation and remodeling, and its relevance to emphysema in COPD patients. Consequently, targeting eosinophil-derived cathepsin L could potentially offer a therapeutic avenue for emphysema patients. Further investigations are warranted to explore therapeutic strategies targeting cathepsin L in emphysema patients.

Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found that FOXP2 is overexpressed in human prostate cancer cells and prostate tumors, but its expression is absent in normal prostate epithelial cells and low in benign prostatic hyperplasia. To date, little is known regarding the link of FOXP2 to prostate cancer. We observed that high FOXP2 expression and frequent amplification are significantly associated with high Gleason score. Ectopic expression of FOXP2 induces malignant transformation of mouse NIH3T3 fibroblasts and human prostate epithelial cell RWPE-1. Conversely, FOXP2 knockdown suppresses the proliferation of prostate cancer cells. Transgenic overexpression of FOXP2 in the mouse prostate causes prostatic intraepithelial neoplasia. Overexpression of FOXP2 aberrantly activates oncogenic MET signalling and inhibitors targeting MET signalling effectively reverts the FOXP2 -induced oncogenic phenotype. Additionally, the novel recurrent FOXP2-CPED1 fusion identified in prostate tumors results in high expression of truncated FOXP2, which exhibit a similar capacity for malignant transformation. Together, our data demonstrate for the first time that FOXP2 is an oncogene involved in tumorigenicity of prostate.

Background: Guben Zhike decoction (GBZKD) is derived from the experience of Professor Enxiang Chao, an esteemed master of Chinese medicine, while treating chronic obstructive pulmonary disease (COPD). GBZKD reinforces the healthy qi and consolidates defensive qi. This study explored the efficacy and potential mechanism of action of GBZKD in a COPD mouse model using proteomics. Methods: A COPD mouse model was established through cigarette smoke exposure and intranasal lipopolysaccharide administration. The model was verified through lung function test and lung histopathological observation. Label-free quantitative proteomics was used to detect the lung tissue proteins of mice from the GBZKD, COPD, and control groups. Results: GBZKD markedly improved the lung function and associated pathological conditions in the COPD mouse model. Proteomic analysis identified 4316 proteins, of which 3696 were quantitative proteins. We highlighted 287 and 184 proteins with significant regulatory roles in the lung tissues of COPD mice and GBZKD-treated mice, respectively. These proteins participated in multiple functions, including complement/coagulation cascade, immune response, and metabolic pathways. Conclusion: GBZKD exhibits multitarget and multipathway therapeutic effects in a COPD mouse model.

Spatial metabolomics can reveal intercellular heterogeneity and tissue organization. Here we report on the spatial single nuclear metabolomics (SEAM) method, a flexible platform combining high-spatial-resolution imaging mass spectrometry and a set of computational algorithms that can display multiscale and multicolor tissue tomography together with identification and clustering of single nuclei by their in situ metabolic fingerprints. We first applied SEAM to a range of wild-type mouse tissues, then delineated a consistent pattern of metabolic zonation in mouse liver. We further studied the spatial metabolic profile in the human fibrotic liver. We discovered subpopulations of hepatocytes with special metabolic features associated with their proximity to the fibrotic niche, and validated this finding by spatial transcriptomics with Geo-seq. These demonstrations highlighted SEAM's ability to explore the spatial metabolic profile and tissue histology at the single-cell level, leading to a deeper understanding of tissue metabolic organization.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by proliferative vascular remodeling. Abnormal vascular smooth muscle cell (VSMC) phenotype switching is crucial to this process, highlighting the need for VSMC metabolic changes to cover cellular energy demand in CTEPH. We report that elevated Wnt family member 5B (WNT5B) expression is associated with vascular remodeling and promotes VSMC phenotype switching via mitochondrial dynamics regulation in CTEPH. Using primary culture of pulmonary artery smooth muscle cells, we show that high WNT5B expression activates VSMC proliferation and migration and results in mitochondrial fission via noncanonical Wnt signaling in CTEPH. Abnormal VSMC proliferation and migration were abolished by mitochondrial division inhibitor 1, an inhibitor of mitochondrial fission. Secreted frizzled‐related protein 2, a soluble scavenger of Wnt signaling, attenuates VSMC proliferation and migration by accelerating mitochondrial fusion. These findings indicate that WNT5B is an essential regulator of mitochondrial dynamics, contributing to VSMC phenotype switching in CTEPH.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic inflammation, emphysema, airway remodeling, and altered lung function. Despite the canonical classification of COPD as a neutrophilic disease, blood and airway eosinophilia are found in COPD patients. Identifying the tools to assess eosinophilic airway inflammation in COPD models during stable disease and exacerbations will enable the development of novel anti-eosinophilic treatments. We developed different animal models to mimic the pathological features of COPD. Our results show that eosinophils accumulated in the lungs of pancreatic porcine elastase-treated mice, with emphysema arising from the alveolar septa. A lipopolysaccharide challenge significantly increased IL-17 levels and induced a swift change from a type-2 response to an IL-17-driven inflammatory response. However, lipopolysaccharides can exacerbate cigarette smoking-induced airway inflammation dominated by neutrophil infiltration and airway remodeling in COPD models. Our results suggest that eosinophils may be associated with emphysema arising from the alveolar septa, which may be different from the small airway disease-associated emphysema that is dominated by neutrophilic inflammation in cigarette smoke-induced models. The characterization of heterogeneity seen in the COPD-associated inflammatory signature could pave the way for personalized medicine to identify new and effective therapeutic approaches for COPD.

Objectives Carotid artery geometry influences blood flow disturbances and is thus an important risk factor for carotid atherosclerosis. Extracellular matrix (ECM) and yes-associated protein (YAP) expression may play essential roles in the pathophysiology of carotid artery stenosis, but the effect of blood flow disturbances of carotid bifurcation location on the ECM is unknown. We hypothesized that carotid artery anatomy and geometry are independently associated with the ECM and YAP expression. Methods In this cross-sectional study, 193 patients were divided into two groups: an asymptomatic group (n = 111) and a symptomatic group (n = 82), symptomatic patients presenting with ischemic attack, amaurosis fugax, or minor non-disabling stroke. For all subjects before surgery, carotid bifurcation angle and internal artery angle were measured with computed tomography angiography (CTA), and laminar shear stress was measured with ultrasonography. After surgery, pathology of all plaque specimens was analyzed using hematoxylin and eosin (HE) staining and Movat special staining. Immunohistochemistry was performed to detect expression of YAP in a subset of 30 specimens. Results Symptomatic patients had increased carotid bifurcation angle and laminar shear stress compared to asymptomatic patients (P < 0.05), although asymptomatic patients had increased internal carotid angle compared to symptomatic patients (P < 0.001). Relative higher bifurcation angles were correlated with increased carotid bifurcation, decreased internal angle, and decreased laminar shear stress. For each change in intervertebral space or one-third of vertebral body height, carotid bifurcation angle changed 4.76°, internal carotid angle changed 6.91°, and laminar shear stress changed 0.57 dynes/cm2. Pathology showed that average fibrous cap thickness and average narrowest fibrous cap thickness were greater in asymptomatic patients than symptomatic patients (P < 0.05). Expression of proteoglycan and YAP protein in symptomatic patients was higher than in asymptomatic patients (P < 0.001), while collagen expression was lower in symptomatic patients than asymptomatic patients (P < 0.05). Conclusion Geometry of the carotid artery and position relative to cervical spine might be associated with ECM and YAP protein expression, which could contribute to carotid artery stenosis.

Objective:To investigate the protective effect of astaxanthin on the retinopathy in rats with type 1 diabetes and related mechanism.Methods:Thirty-six male SPF rats received intraperitoneal injection of 1% streptozotocin (STZ) to prepare type 1 diabetes model.The rats were randomly assigned to the diabetes group, low dose astaxanthin group and high dose astaxanthin group by a random number table.The rats in the low dose astaxanthin group and high dose astaxanthin group received respectively astaxanthin 20 mg/kg and 100 mg/kg by gavage everyday.The rats in the diabetes group received an equal volume of olive oil.Twelve rats received an equal volume of sodium citrate as the control group.Blood glucose and body mass were measured every 2 weeks.After 24 weeks, the retina was digested to make retinal capillary network preparation.The number of pericytes and acelluar strands was compared among the different experimental groups.The relative expressions of anti-inflammatory cytokines in retinal tissue were detected by immunohistochemistry, real-time PCR and Western blot.The use and care of the animals complied with Regulations for the Administration of Affair Concerning Experimental Animals by State Science and Technology Commission.Results:Body mass of the rats in the low dose astaxanthin group and high dose astaxanthin group was significantly higher than that in the diabetes group (both at P<0.05). Blood glucose levels in the low dose astaxanthin group and high dose astaxanthin group were significantly lower than that in the diabetes group (both at P<0.05). In the control group, main artery was round, uniform, and strongly stained.The vein was lightly stained and had a large diameter.In the diabetes group, retinal arteriovenous trunk and branches appeared tortuous at a low magnification, with capillary network disorder.The morphology of the capillaries showed pathology in the low dose astaxanthin group and high dose astaxanthin group, but the vascular tortuosity, dilatation and stenosis were reduced in comparison with the diabetes group.The number of pericytes was 466.4±23.2, 207.3±31.7, 298.1±27.1 and 312.2±19.5 among different groups, with a significant difference among them ( F=34.420, P=0.047). The number of acelluar strands were 5.2±2.3, 32.9±12.7, 14.5±9.1 and 16.5±3.5 among different groups, with a significant difference among them ( F=47.340, P=0.021). The relative expression of IL-6, TNF-α and caspase-3 mRNA in the low dose astaxanthin group was 0.87±0.23, 0.91±0.34 and 1.07±0.15, the relative expression in the high dose astaxanthin group was 0.81±0.31, 0.85±0.39 and 0.95±0.11, which was significantly decreased in comparison with the diabetes group (1.63±0.47, 1.57±0.53 and 1.51±0.32) (all at P<0.05). The relative expression of IL-6, TNF-α and caspase-3 protein in the low dose astaxanthin group was 0.63±0.33, 0.51±0.14 and 0.60±0.13, the relative expression in the high dose astaxanthin group was 0.69±0.22, 0.49±0.15 and 0.57±0.22, which was significantly decreased in comparison with the diabetes group (all at P<0.05). Conclusions:Astaxanthin may play an important role in protecting pericytes from apoptosis and delaying development and progression of diabetic retinopathy in rats.Additionally, astaxanthin can inhibit release of anti-apoptosis and anti-inflammatory cytokines.

AIMS:Our previous study has demonstrated that porcine diazepam-binding inhibitor (pDBI) and its active fragments, pDBI-16 and pDBI-19, have inhibition effect on morphine analgesia in mice. The present study aimed to investigate the underlying mechanism and potential application of this anti-opioid effect.MATERIALS AND METHODS:Effect of DBI on morphine analgesia was examined by the tail electric stimulation vocalization test. Complementary peptides and antiserum were used to further confirm the effect of DBI in morphine tolerance and dependence. Pharmacological and microinjection methods were used to investigate the underlying mechanism.KEY FINDINGS:Firstly, pDBI administered either intracerebroventricularly or intravenously dose-dependently inhibited morphine analgesia, while blocking DBI-16 or DBI-19 by the complementary peptides for DBI-16 (CP-DBI-16) or DBI-19 (CP-DBI-19) potentiated it in mice. Secondly, explicit immunoexpression of DBI in the lateral habenular (LHb) was observed in naive rats, and intra-LHb injection of pDBI dose-dependently abolished analgesic effect produced by intra-periaqueductal gray (PAG) injection of morphine in rats. Thirdly, pretreatment with N-Methyl-d-Aspartate receptor (NMDAR) antagonist MK-801 or nitric oxide (NO) synthase inhibitor L-NAME abolished the inhibition effect of pDBI, pDBI-16 or pDBI-19 on morphine analgesia in mice. Finally, antiserum against DBI dose-dependently reversed analgesic tolerance induced by increasing doses of morphine twice daily for 13 days in mice, while CP-DBI-16 or CP-DBI-19 significantly inhibited naloxone-precipitated morphine withdrawal jumping in mice.SIGNIFICANCE:Taken together, our results demonstrated that NMDAR/NO signaling and LHb-PAG pathway are crucially involved in the anti-opioid effect of DBI, which could provide a potential biological target for opioid tolerance and dependence.

Background: Tanshinone IIA (Tan IIA), a lipophilic constituent from Salvia miltiorrhiza Bunge, has shown a promising cardioprotective effect including anti-atherosclerosis. This study aims at exploring Tan IIA's anti-inflammatory and immune-regulating roles in stabilizing vulnerable atherosclerotic plaque in ApoE-deficient (ApoE-/-) mice. Methods: Male ApoE-/- mice (6 weeks) were fed with a high-fat diet for 13 weeks and then randomized to the model group (MOD) or Tan IIA groups [high dose: 90 mg/kg/day (HT), moderate dose: 30 mg/kg/day (MT), low dose: 10 mg/kg/day (LT)] or the atorvastatin group (5 mg/kg/day, ATO) for 13 weeks. Male C57BL/6 mice (6 weeks) were fed with ordinary rodent chow as control. The plaque stability was evaluated according to the morphology and composition of aortic atherosclerotic (AS) plaque in H&E staining and Movat staining sections by calculating the area of extracellular lipid, collagenous fiber, and foam cells to the plaque. The expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor88 (MyD88)/nuclear factor-kappa B (NF-κB) signal pathway in aorta fractions was determined by immunohistochemistry. Serum levels of blood lipid were measured by turbidimetric inhibition immunoassay. The concentrations of tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were detected by cytometric bead array. Results: Tan IIA stabilized aortic plaque with a striking reduction in the area of extracellular lipid (ATO: 13.15 ± 1.2%, HT: 12.2 ± 1.64%, MT: 13.93 ± 1.59%, MOD: 18.84 ± 1.46%, P < 0.05) or foam cells (ATO: 16.05 ± 1.26%, HT: 14.88 ± 1.79%, MT: 16.61 ± 1.47%, MOD: 22.08 ± 1.69%, P < 0.05) to the plaque, and an evident increase in content of collagenous fiber (ATO: 16.22 ± 1.91%, HT: 17.58 ± 1.33%, MT: 15.71 ± 2.26%, LT:14.92 ± 1.65%, MOD: 9.61 ± 0.7%, P < 0.05) to the plaque than that in the model group, concomitant with down-regulation of the protein expression of TLR4, MyD88, and NF-κB p65, and serum level of MCP-1 and TNF-α in a dose-dependent manner. There were no differences in serum TC, LDL, HDL, or TG levels between ApoE-/- mice and those treated with atorvastatin. Conclusions: These results suggest that Tan IIA could stabilize vulnerable AS plaque in ApoE-/- mice, and this anti-inflammatory and immune-regulating effect may be achieved via the TLR4/MyD88/NF-κB signaling pathway.

Retinal hypoperfusion injury is the pathophysiologic basis of ocular ischemic syndrome (OIS) which often leads to severe visual loss. In this study, we aimed to establish a rat model of retinal chronic hypoperfusion by bilateral common carotid artery occlusion (BCCAO) and observe changes in the retinal function and morphology. We found that model rats showed retinal arteriosclerosis, slight dilated retinal vein, small hemangiomas, hemorrhages, vascular segmental filling, and nonperfused areas after 2 weeks of BCCAO. In the model rats, the retinal circulation time was significantly prolonged by fluorescein fundus angiography (FFA), the latency of a and b waves was delayed and the amplitude was decreased significantly at each time point by electroretinogram (ERG), and the perfusion of the eyes continued to reduced. Morphologic and ultrastructural changes covered that the retinal ganglion cells (RGCs) presented obvious apoptosis and the thickness in the retinal layers were significantly thinner. Collectively, these findings suggested that BCCAO induced retinal hypoperfusion injury in the model rats, thus providing an ideal animal model for the study of OIS.

Objective: To investigate the effects of tanshinone ⅡA on atherosclerosis plaque formation and adventitial mast cells activation in high-fat-diet induced Apo E(-/-) mice model. Methods: Sixteen 8-week-old Apo E(-/-)male mice and eight 8-week-old C57BL/6 male mice were randomly allocated into following group: the control group (C57BL/6 + carboxymethyl cellulose per gavage), the atherogenic group (Apo E(-/-)+carboxymethyl cellulose per gavage) and the tanshinoneⅡA intervention group (Apo E(-/-)+30 mg/kg tanshinone ⅡA per gavage). All three groups were fed with high-fat-diet for 26 weeks. Tanshinone ⅡA/carboxymethyl cellulose was applied by the method of gavage administration 6 weeks before execution. After 26 weeks, tumor necrosis factor-α (TNF-α) andinterleukin (IL)-6 levels in serum were assessed by ELISA. Carotid artery was removed, fixed with paraformaldehyde, embedded with paraffin and sectioned. Percentage of stenosis was evaluated on HE stained sections. Plaque progression was assessed by Movat staining. Toluidine blue staining was used to evaluate mast cells infiltration and activation. Immunochemistry staining was used to assess 5-HT, TNF-α and IL-6 expression. mRNA expression of mast cell marker Fcer1a in adventitial tissue was detected by real time-PCR. Results: After high-fat-diet for 26 weeks, the mice in the atherogenic group showed advanced atherosclerosis, tanshinoneⅡA intervention reduced the percentage of carotid artery stenosis caused by atherosclerotic plaque formation ((58.48±8.07)% vs. (80.31±4.08)%, P<0.05). Compared with the atherogenic group, tanshinone ⅡA intervention group had lower level of TNF-α ((12.39±1.62)pg/ml vs. (17.44±1.42)pg/ml) and IL-6 ((116.24±12.16)pg/ml vs. (166.05±19.09)pg/ml) in serum, lower TNF-α ((20 145±1 556) vs. (25 288±1 671)) and IL-6 ((25 688±1 604) vs. (35 286±4 198)) expression in adventitia (all P<0.05). TanshinoneⅡA intervention also decreased the number of mast cells infiltration and activation, reduced 5-HT expression and mast cell marker Fcer1a mRNA relative expression in adventitia (all P<0.05). Conclusions: Tanshinone ⅡA could attenuate induced by high-fat-diet carotid artery atherosclerosis in Apo E(-/-) mice. The protective effect of tanshinoneⅡA is probably mediated through reducing the number and activation percentage of mast cells, decreasing the release of inflammatory cytokines and inflammation of carotid artery in adventitia.

OBJECTIVE:Varicose veins are a common problem worldwide and can cause significant impairments in health-related quality of life, but the etiology and pathogenesis remain not well defined. This study aims to elucidate transcriptomic regulations of varicose veins by detecting differentially expressed genes, pathways and regulator genes.METHODS:We harvested great saphenous veins (GSV) from patients who underwent coronary artery bypass grafting (CABG) and varicose veins from conventional stripping surgery. RNA-Sequencing (RNA-Seq) technique was used to obtain the complete transcriptomic data of both GSVs from CABG patients and varicose veins. Weighted Gene Co-expression network analysis (WGCNA) and further analyses were then carried out with the aim to elucidate transcriptomic regulations of varicose veins by detecting differentially expressed genes, pathways and regulator genes.RESULTS:From January 2015 to December 2016, 7 GSVs from CABG patients and 13 varicose veins were obtained. WGCNA identified 4 modules. In the brown module, gene ontology (GO) analysis showed that the biological processes were focused on response to stimulus, immune response and inflammatory response, etc. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that the biological processes were focused on cytokine-cytokine receptor interaction and TNF signaling pathway, etc. In the gray module, GO analysis showed that the biological processes were skeletal myofibril assembly related. The immunohistochemistry staining showed that the expression of ASC, Caspase-1 and NLRP3 were increased in GSVs from CABG patients compared with varicose veins. Histopathological analysis showed that in the varicose veins group, the thickness of vascular wall, tunica intima, tunica media and collagen/smooth muscle ratio were significantly increased, and that the elastic fiber/internal elastic lamina ratio was decreased.CONCLUSION:This study shows that there are clear differences in transcriptomic information between varicose veins and GSVs from CABG patients. Some inflammatory RNAs are down-regulated in varicose veins compared with GSVs from CABG patients. Skeletal myofibril assembly pathway may play a crucial role in the pathogenesis of varicose veins. Characterization of these RNAs may provide new targets for understanding varicose veins diagnosis, progression, and treatment.

Background and objective:Bevacizumab (BVZ) is a recombinant humanized antibody that inhibits the vascular endothelial growth factor A (VEGFA) and is used for the treatment of various types of cancer. BVZ is primarily given by the intravenous drip (I.V.), which often leads to low efficacy and various side effects. Therefore, the present study was to evaluate the effect of local delivery of BVZ against triple-negative breast cancer (TNBC) xenograft tumors.Methods:Mice 4T1 TNBC cells were engrafted in female BALB/c mice. After the tumors reached about 5 mm (diameter), animals were treated with BVZ through the local injection from four directions around the tumors. The tumor growth, survival and potential mechanisms of action were evaluated.Results:The growth and microvessel density of engrafted tumors were dramatically reduced with the tumor inhibition rate of 32.8 ± 3%. No obvious side effects were observed. The expression of VEGFA, VEGF receptor (VEGFR), matrix metalloproteinase (MMP)-2, MMP-9, Delta-like ligand 4 (DLL4) and Integrin-5 was significantly reduced in TNBC tumor tissues. In contrast, tissue inhibitor of matrix metalloproteinase (TIMP)-2 was significantly upregulated in xenograft tumors. Additionally, local delivery of BVZ led to the reduction of VEGFA and tumor necrosis factor (TNF)-alpha in the serum. Protein-protein interaction (PPI) analysis revealed that the proteins altered by the local delivery of BVZ were associated with angiogenesis and regulation of cell migration.Conclusion:This study provided evidence associated with local delivery of BVZ against TNBC tumors supporting the use of BVZ local injections to overcome some of the disadvantages associated with I.V. therapy with BVZ.

Objective To explore the effect of angiogenesis in carotid atherosclerotic plaque.Methods From Jan 2016 to Aug 2016,Carotid artery plaque was abtained in 52 cases after carotid endarterectomy at the Department of Cardiovascular Surgery of China-Japan Friendship Hospital.Patients were divided into symptomatic group and asymptomatic group.Specimens were stained with HE and Movat,and the density,size,distribution and morphology of neovascularization were counted.Results The density of neovascularization in the symptomatic group and the asymptomatic group were 5.27 ± 0.46 and 2.30 ±0.29,respectively (P ＜ 0.001),the average cross-sectional area of neovascularization in the symptomatic group was (2.26±0.21) mm2 and (1.00 ±0.48) mm2 in the asymptomatic group (P=0.02).In the distribution,the symptomatic group and the asymptomatic group were 3.37 ± 0.46/ mm2,1.32 ±0.16/mm2 in basal part,3.71 ±0.42/mm2,1.56 ±0.20/mm2 in the shoulder part,3.48 ±0.44/mm2,1.55 ± 0.21/ mm2 in the fibrous cap,respectively (P ＜ 0.001).Conclusion The density and cross-sectional area of neovascularization in the symptomatic group were larger than those in the asymptomatic group,irregular branching vessels were dominant.